Genetics and physiopathology of muscle tissues

Aged heart is characterized by a progressive loss of cardiomyocytes and hypertrophy of remnant cardiomyocytes associated with increased fibrosis and ventricular wall stiffness while aged skeletal muscles are characterized by fiber atrophy, loss of regenerative potential and weakness (sarcopenia), and increased fat/lean mass ratio (sarcopenic obesity). Mitochondria and energy maintenance play a fundamental role in the muscle aging process.

A key aspect of energy metabolism in muscle tissues is the complex interaction between the cytoskeleton and the energy units formed by mitochondria, glycolytic complexes and energy transfer systems such as the phosphocreatine shuttle. Although remodeling of the cell architecture co-occurs with remodeling of the energy metabolism in diseases, such as heart failure or muscle wasting, little is known on the homeostatic regulators of this coupling between cytoskeleton and energy metabolism. Our research aims are to improve the knowledge on the mechanisms that dictate the pace and severity of age-associated decline of cardiac and muscular tissues, to find new diagnostic and therapeutic strategies for the palliation of these disorders.

More...

Aging is characterized by a progressive functional and structural decline in muscle tissues. In the aging heart, there is a progressive loss of cardiomyocytes and hypertrophy of remnant cardiomyocytes associated with increased fibrosis and ventricular wall stiffness.

On the other hand, aged skeletal muscles are characterized by fiber atrophy, loss of regenerative potential and weakness (sarcopenia) while the fat/lean mass ratio tends to gradually increase with age. Reduced oxidative phosphorylation capacity and subsequent decline in ATP generation in elderly humans suggest a fundamental role of mitochondria and energy maintenance in the muscle aging process. 

A key aspect of energy metabolism in muscle tissues is the complex interaction between the cytoskeleton including intermediate filaments (IF), microtubule and actin filament, and the energy units formed by mitochondria, glycolytic complexes and energy transfer systems such as the phosphocreatine shuttle. 

Although remodeling of the cell architecture co-occurs with remodeling of the energy metabolism in diseases, such as heart failure or muscle wasting, little is known on the homeostatic regulators of this coupling between cytoskeleton and energy metabolism. Our research aims are to improve the knowledge on the mechanisms that dictate the pace and severity of age-associated decline of cardiac and muscular tissues, to find new diagnostic and therapeutic strategies for the palliation of these disorders. 

Highlights

We developed several mouse models of muscle and cardiovascular diseases due to either conditional Cre-LoxP mutations of transcription factor SRF, or knock-out of genes coding IF proteins. Our research on SRF highlighted its pivotal role as regulator of arterial smooth muscle cell contractility and endothelial cells angiogenic capacities. In the heart, we showed that SRF is a co-regulator of genes and microRNAS involved in cytoskeleton and energy metabolism in cardiomyocytes. Combined down-regulation of contractile proteins and MCK following SRF inactivation perturb the organization of desmin IF that becomes a major target of oxidative stress in the failing heart. We studied the role of desmin IF in the maintenance of tissue architecture and mitochondria integrity.

Recent results show that IFs like Desmin, Vimentin and Synemin are key cytoskeleton proteins involved in the control of muscle growth and energy homeostasis. We developed mouse models of muscle wasting induced by chronic disease like cancer to study the efficiency of endurance exercise and pharmacological treatments activating pathways such as AMPK and PPAR to stimulate muscle growth and oxidative metabolism.

Future directions

In the future, we aim:

  • to address the role of new targets identified by proteomic and transcriptomic screens in our mouse models with a focus on those likely to play a role in the coupling of cytoskeleton and energy metabolism and able to control cell hypertrophy. Those include new players like microRNAs miR-378/miR-378* that we found to repress cytoskeletal proteins like vimentin and actin as well as proteins involved in energy metabolism and transcriptional repressors like CTIP2.
  • to characterize the unsuspected impact of IF proteins on global energy expenditure and balance between adipose and muscle tissue. Our research suggests a potential role of IF in sarcopenic obesity. Our different IF KO models will be subjected to either high-fat diet or fasting protocols as well as aging studies. We will perform full metabolic profiles to understand the role of IF on mitochondrial functions, energy storage and mobilization process.
  • to extend our expertise cancer cachexia to the study of sarcopenia and heart failure cachexia in aged mice. We will address on one hand the role of satellite cells impediment in this process with a focus on key transcriptional regulators such as Pax7, Id3 and SRF and the role of cytoskeletal element and mechanotransduction of exercise-mediated SRF activation.
  • study the role of the zinc finger transcriptional repressor protein Bcl11b in cardiac hypertrophy and its role in stem cell commitment and differentiation into the cardiac lineage.

Collaborations

International collaborations

Role of SRF in heart

  • -Dr. C Brenner University of Iowa, USA
  • -Dr. G Tarone, Turin University, Italie
  • Role of SRF in angiogenesis
  • - Dr. M Fruttiger University College London, UK
  • - Dr. H Gerhardt Cancer Research, London, UK
  • Role of SRF in smooth muscle cells
  • - Dr. R Feil Pharmacology and Toxicology Institute, München, AllemagneSynemin expression in nerve system and stem cells
  • - Pr. V Moura-Neto Universidade Federal do Rio de Janeiro, Brazil
  • - Pr. R Robson University of Iowa USA
    Mechanisms underlying cachexia
  • - Pr. S Adamo Sapienza University of Rome, Italie
  • - Pr. M Rocchi, University of Urbino (IT)
  • - Pr. D Guttridge, Ohio State University, Columbus (OH), USA
  • - Pr. U Carraro, University of Padua (IT)
  • - Dr. M Tatullo, Calabrodental Clinic, Crotone (IT)

National collaborations

  • -Dr. B Escoubet, INSERM Hôpital Bichat
  • -Dr. P Lacolley, INSERM U961, Nancy
  • -Dr. L Loufrani, INSERM Angers
  • -Pr. A Ferry, Institut de Myologie, Paris
  • -Dr. JL Samuel, INSERM, Paris
  • -Dr. Ventura-Clapier, INSERM Chateney-Malabry;
  • -Prs. B Friguet and O Agbulut, UPMC